Abstract
We hypothesize that a cylinder implant made of multilayer Poly-lactic-co-glycolic-acid (PLGA) membrane can be a method for controlled and extended drug release. We fashioned a multilayer cylindrical implant termed STID100 that released doxorubicin for 3 weeks in an orthotopic 4T1 breast cancer model in Balb/C mice. This implant starts as a thin doxorubicin-embedded PLGA membrane, and is then rolled into a cylinder containing an air gap between the membrane layers. Its controlled sustained release delivered 2× the amount of the intravenous (IV) equivalent of doxorubicin, inhibited the primary tumor, and prevented lung metastasis. Importantly it did not cause weight loss, splenomegaly, or cardiac toxicity vs systemically administrated doxorubicin. This favorable safety profile is further substantiated by the finding of no detectable plasma doxorubicin in multiple time points during the 3-week period, and low tumor doxorubicin concentration. The implant system delivered to the specification of an ideal pharmacological paradigm might offer a better coverage of the local tumor, significantly preventing metastatic spread with less drug toxicity to many vital organs, compared to the traditional pharmacology of IV route. The profile of STID made it an attractive therapeutic alternative in metastatic tumor prevention, pain management and many other diverse clinical scenarios.
Highlights
A therapeutic implant for localized disease should have many advantages over its IV or oral equivalent: minimal systemic side effects; elimination of daily dosing and maintenance of steady state drug concentration; better patient comfort and compliance, and only local drug delivery [1] [2]
We developed a simpler system to construct a solid therapeutic implant device with layered Poly-lactic-co-glycolic-acid copolymer (PLGA) membranes
One of the major concerns using implants containing a high dose of chemotherapy agent is local tissue irritation, skin degradation, and inability to heal the surgical site
Summary
A therapeutic implant for localized disease should have many advantages over its IV or oral equivalent: minimal systemic side effects; elimination of daily dosing and maintenance of steady state drug concentration; better patient comfort and compliance, and only local drug delivery [1] [2]. The translation of those technologies into useful treatments has been slow to realize To address these deficiencies, we developed a simpler system to construct a solid therapeutic implant device with layered PLGA membranes. We developed a simpler system to construct a solid therapeutic implant device with layered PLGA membranes. Our prototype starts with a panel of thin PLGA membrane with the drug of interest evenly distributed inside the membrane It is rolled from one end into a multilayered cylinder in one simple step at or near room temperature. Rate of release ∝ Diffusion coefficient of the therapeutic for the intermaterail crosssection Number of intermateral crosssections Another advantage of our multilayered solid therapeutic implant device (STID) is its simplicity of construction. We found a construct that achieved these goals: effective suppression of tumor growth with minimal systemic side effect; and an initial pharmacological profile close to an ideal paradigm
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